Children's Research Institute
Project Term: October 12, 2017 - September 30, 2021
Hodgkin’s Lymphoma (HL) is unique that the tumor cells are surrounded by an inhibitory environment that is able to evade effective anti-tumor responses. Understanding this environment may be a window into effective combination immunotherapies. The goal of this project is to determine if current immunotherapies can change this tumor environment sufficiently to unleash pre-existing anti-tumor T-cell immune responses to allow a more successful incorporation of HL specific cytotoxic T cells.
Hodgkin’s lymphoma (HL), a type of blood cancer is largely curable but with significant long-term side effects. Moreover 10-20% of patients are resistant to treatment and difficult to cure. HL is unique that the tumor cells are surrounded by an inhibitory environment that makes the immune system dysfunctional and allows evasion from an effective anti-tumor response. Understanding this environment may provide insight into how we can spur the immune system to attack HL cells effectively. Like many cancer cells, HL cells escape the immune attack by expressing a protein called PD1 or PDL-1, which is is normally expressed by healthy T cells to prevent them from attacking healthy cells. PD1-inhbitors are drugs that can bind to the PD-1/PDL-1 on lymphoma cells thereby releasing the “brakes” on the immune system to mount a strong attack on the HL cells. The lymphoma cells also secrete certain chemicals like TGFβ which incapacitates the immune cells to kill the lymphoma cells effectively. The goal of this project is to understand how we can change the tumor microenvironment sufficiently to unleash pre-existing anti-tumor immune responses and allow more successful incorporation of killer- T cells. We will determine if PD1 inhibitors when given in combination with the administration of a novel cancer killing T-cell therapy will produce long-lasting cures in patients with high risk HL with less side effects than conventional chemotherapy. Finally, we will continue to improve the efficacy of our combination immunotherapy approach by also engineering the cancer killing T cells to become resistant to the inhibitory chemical TGFβ which is released by the HL tumor cells and has devastating effects on T cell function in vivo. In the laboratory we will determine if these engineered T cells have enhanced killing ability compared to the non engineered T cells.